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CAS No. : | 3674-06-4 | MDL No. : | MFCD00037911 |
Formula : | C18H22N2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NHUCANAMPJGMQL-ZDUSSCGKSA-N |
M.W : | 362.38 | Pubchem ID : | 107447 |
Synonyms : |
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 95.18 |
TPSA : | 102.01 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.13 cm/s |
Log Po/w (iLOGP) : | 2.85 |
Log Po/w (XLOGP3) : | 1.95 |
Log Po/w (WLOGP) : | 1.35 |
Log Po/w (MLOGP) : | 1.62 |
Log Po/w (SILICOS-IT) : | 1.55 |
Consensus Log Po/w : | 1.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.89 |
Solubility : | 0.465 mg/ml ; 0.00128 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.72 |
Solubility : | 0.0695 mg/ml ; 0.000192 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.67 |
Solubility : | 0.0782 mg/ml ; 0.000216 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.76 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In dichloromethane; at -5℃; | General procedure: A round-bottom flask was charged with amino acid (2.5 mmol), NaHCO3 (5 mmol, or 7.5 mmol in the case of using TFA salt of amino acid) and THF-H2O (1:1,20 mL). A solution of succinimide-activated amino acid (2.75 mmol) in THF (15 mL) was added dropwise to the mixture, and the reaction was stirred at rt for 1-2 days. THF was removed on a rotary evaporator, the reaction mixture was acidified with 0.5 M HCl to pH 2, and the product was extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with water and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the product was purified by column chromatography on silica gel. | |
With dicyclohexyl-carbodiimide; at 0℃; | General procedure: The general scheme for the synthesis of AA-CAMderivatives is shown in Fig. S1 and the details ofchemical synthesis are provided in the SupplementaryMethods section. CAM [(1R,2R)-2-amino-1-(4--nitrophenyl)propane-1,3-diol)] was prepared asdescribed previously [23]. Amino acids with protectedalpha- and side-chain amino groups wereactivated by reaction with N-hydroxysuccinimide inthe presence of N,N?-dicyclohexylcarbodiimide at0 C. The resulting succinimide-reactive esters wereused for the acylation of CAM in the presence ofdiisopropylethylamine as a base at room temperature.Subsequent deprotection was achieved bytreatment of the obtained amino-acid CAM derivativeswith trifluoroacetic acid and appropriate scavengers.Synthesized AA-CAM derivatives were purifiedby columnchromatography on silica gel using suitablesystems of solvents. For generating N-acetylatedvariants of AA-CAM, additional acetylation wasperformed by reacting the unprotected AA-CAMderivatives with the N-acetylsuccinimide. Purity andchemical structures of obtained compounds wereconfirmed by HPLC, LC-MS, and NMR spectroscopy(see Supplementary Methods). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetonitrile at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Phe-Amp was synthesized by a similar method (see FIG. 5) except the amino acid starting material was <strong>[3674-06-4]Boc-Phe-OSu</strong>.[0188] Phe-Amp hydrochloride: hygroscopic; Eta NMR(400 MHZ, DMSO-^): delta 8.82 (d,J=8.0 Hz, IH), 8.34 (bs, 3H), 7.29-7.11 (m, 10H), 3.99 (m, 2H), 2.99 (dd, J=13.6, 6.2 Hz,IH), 2.88 (dd, J=13.6, 7.2 Hz, IH), 2.64 (dd, J=13.2, 7.6 Hz, IH), 2.53 (m, IH), 1.07 (d,J=6.4 Hz, 3H); 13C NMR (100 MHz, DMSO-^5): delta 167.31, 139.27, 135.49, 130.05, 129.66,128.78, 128.61, 127.40, 126.60, 53.83, 47.04, 42.15, 37.27, 20.54; HRMS: (ESI) forC18H23N2O (M+H)+: calcd, 283.1810: found, 283.1806. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; ethyl acetate; citric acid; | 3.3 g mmol (ITA) Phe-Phe-Tyr-OC2H5 and 5 mmol Z-Gly-Osu was mutually dissolved in 10 ml of anhydrous THF (solvent). The solution was neutralized with N-methylmorpholine pH8.0 and then stirred for 72 hours at room temperature. After rotary evaporation to powder, the powder was dissolved in ethyl acetate and washed three times in turn with 10% citric acid, 1% potassium carbonate, saturated sodium chloride. The residue was dried with anhydrous sodium sulfate for 2 hours and again rotary evaporated to an exceedingly small volume. The solution then became muddy from clear then clear again after the addition of a large amount of ether. A grey yellow precipitate formed after standing at room temperature for 72 hours. The precipitate was 2 g (87%) after washing with ether and drying, the precipitate had a melting point at 148-151 . The product was homogeneous in thin layer chromatography (3/7 system). 2.6 Preparation of ZGly-Phe-Phe-Tyr-NHNH2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of oxycodone-freebase (l.Oeq) in tetrahydrofuran (THF) (lOml/mmol) was added K-O-t-butoxide (l.leq) or LiN(TMS)2 (1-leq). After 5 minutes, <strong>[3674-06-4]Boc-Phe-OSu</strong> (l.leq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with NH4Cl, diluted with EtOAc, and solvents removed. Crude protected product was purified using chromatography. Deprotection occurred with 4N HCl in dioxane (20ml/mmol) to obtain Phe-Oxycodone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; | To a solution of BocPheOSu (1.5g, 4.14mmol, leq) in DCM (10.3 mL) and DMF (10.3 mL) was added H-Lys(Fmoc)-OH (1.84g, 4.55 mmol, l.leq) followed by DIEA (2.9 mL, 16.56 mmol, 4eq). The resulting reaction mixture was stirred overnight and diluted with ethyl acetate. The solution was washed with water (30 mL x 2) and by brine (30 mL x 2). The organic layers were combined, dried over MgSO4 and concentrated in vacuo to yield a yellow residue. The crude residue was then chromatographed over silica gel using CHCl3-MeOH (3:1, v/v) to give the product. MS. [M+l]+ 616. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | A solution OF N-BOC-L-PHENYLALANINE-N-HYDROXUSUCCINIMIDE ester (400 mg, 1.1 mmol) in a mixture of ethanol (6 ML) and 1,4-dioxane (4 ML) was added to a solution of L-Phe-Homotaurine (273 mg, 1.0 mmol) in 1N NAOH (1. 05 mL), water (3 mL) and ethanol (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the solid (601.9 mg) was suspended in a mixture of acetone (8 mL) and isopropanol (0.2 mL) and stirred overnight at room temperature. The mixture was heated under refluxed for 30 minutes and then was cooled to room temperature. The white solid was collected by filtration, washed with ether, then dried in the vacuum oven for 45 minutes. The resulting solid (423.1 mg) was dissolved in a mixture of water/tert-butanol (7: 3,5 mL) and treated with Amberlite IR- 120 plus (washed, 15 g dry weight) for 2 minutes at room temperature. The resin was removed by filtration and washed 3 times with the mixed solvents of water and tert- butanol (10 mL). Concentrated HC1 (4 ML) was added. The solvents were removed under reduced pressure, and the resulting solid was dried in vacuum. The compound was purified by recrystallization from a mixed solvent OF THF and MeOH. The resulting solid was heated under reflux in methanol (about 3 mL) to remove the yellowish color. The solid was dried in vacuo. Compound X was obtained as white solid (84.4 mg, 20%). THE H and 13C NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In dichloromethane; at 0 - 20℃; | A solution OF N-T-BOC-L-PHE N-hydroxysuccinimide ester (2.80 mmol, 1. 01 g) in dichloromethane (12 ML) was added to a cold (0 C) solution of 3-aminopropane-1- sulfonyl-L-Phe-OEt (2.66 mmol, 839 mg) in dichloromethane (10 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane, and washed with 2N HC1, aqueous saturated NaHC03, and brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was applied on flash column chromatography on silica gel (2% MeOH in CHC13). A portion of the pure desired material (600 mg) was isolated. The remaining product was mixed with 40% of the SUCCINIMIDE. Some 3- aminopropanol (70 pL) was added to the mixture that was dissolved in dichloromethane (8 mL) and cooled to 0 C. The mixture was stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane, and washed with 2N HC1, aqueous saturated NAHCO3, brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel (2% MeOH in CHC13). ANOTHER portion of the pure desired material (432.4 mg) was isolated along with the adduct of the succinimide and 3- aminopropanol (220.6 mg, 0. 684 mmol). Compound Y was obtained as a white crystalline foamy solid (1030 mg, 1.83 mmol, 65%). THE H and 13C NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In ethyl acetate; at 20℃; for 20h; | To a solution of 1-octylamine (0.9 g, 6.9 mmol) and triethylamine (0.7 g, 6.9 mmol) in ethyl acetate (80 ml) was added a solution of BOC-Phe-OSU (2.5 g, 6.9 mmol) in ethyl acetate (50 ml). The mixture was stirred at room temperature for 20 hours. The organic layer was washed with water, 10% sodium carbonate, water and brine and dried on MgSO4. Evaporation of the solvent in vacuo yielded MdL080 as a white powder (2.5 g, 6.6 mmol, 96%). 1H NMR (CDCl3): delta = 7.26-7.14 (m, 5H), 5.59 (bp 1H), 5.02 (bp, 1H), 4.20 (m, 1H), 3.07 (m, 4H), 1.57-1.17 (m, 21H), 0.82 (t, 3H, 3J = 6.8 Hz); 13C NMR (CDCl3): delta = 170.98, 136.68, 129.19, 128.50, 126.76, 55.88, 39.34, 38.71, 31.66, 29.21, 29.07, 28.16, 26.64, 22.52, 13.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; | EXAMPLE (82) (2S)-2-[(tert-butoxy)carbonylamino]-N-{4-[(4-hydroxy-9,10-dioxoanthryl)amino]cyclohexyl}-3-phenylpropanamide. [Method 4] Prepared by the reaction of anthraquinone-spacer compound (80) and N-tertiarybutoxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester in THF and triethylamine (1 eq). FABMS(+) m/z: 606 (5%), 584 (100%)(MH)+. M, 583. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 0.55 g (5 mmol) of p-aminobenzylalcohol and 2.0 ml of triethylamine in 30 ml of chloroform, a solution of 2 g (5.5 mmol) of N-t-BOC-L-phenylalanine N-hydroxysuccinimidyl ester (Sigma Chemical Company, St. Louis, MO; product number B1880) in 20 ml of chloroform is added dropwise at 0 DEG C. The mixture is allowed to warm up to room temperature, and then is poured into 50 ml of 5% aqueous HCI. After stirring the aqueous mixture for 4 hours at room temperature, the organic layer is separated and discarded, and the aqueous layer is extracted twice with 30 ml of chloroform. The aqueous layer is evaporated to dryness under vacuum to leave the product L-phenylalanine amide of p-aminobenzylalcohol hydrochloride salt as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 0.9 g (5 mmol) of p-phenylenediamine dihydrochloride and 2.0 ml of triethylamine in 30 ml of chloroform, a solution of 2 g (5.5 mmol) of N-t-BOC-L-phenylalanine N-hydroxysuccinimidyl ester (Sigma Chemical Company, St. Louis, MO; product number B1880) in 20 ml of chloroform is added dropwise at 0 DEG C. The mixture is allowed to warm up to room temperature, and then is poured into 50 ml of 5% aqueous HCI. After stirring the aqueous mixture for 4 hours at room temperature, the organic layer is separated and discarded, and the aqueous layer is extracted twice with 30 ml of chloroform. The aqueous layer is evaporated to dryness under vacuum to leave the product L-phenylalanine amide of p-phenylenediamine hydrochloride salt as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 3,3-dihydroxypropanenitrile; | 1. t-Butyloxycarbonyl-L-phenylalanyl-L-leucine amide. L-Leucine amide hydrochloride (500 mg, 2.99 mmol), t-butyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester (1069 mg, 2.95 mmol), and 0.41 ml (2.95 mmol) triethylamine were dissolved in 10 ml acetonitrile-methanol (1:1, v:v). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure at 40 C. and the residue extracted into ethyl acetate. The extract was washed successively with saturated NaHCO3, water, 10% citric acid, and water. The organic layer was dried with Na2 SO4 and the solvent removed by rotary evaporation as above. The dried product weighed 0.94 g (83.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; hexane; dichloromethane; water; ethyl acetate; | EXAMPLE 1 17.2 g of L-serine methyl ester hydrochloric acid salt were dissolved in 200 ml of dichloromethane and to this solution 15.4 ml of triethylamine was added. To this mixture an homogeneous solution of 36.2 g of tert-butyloxycarbonyl-L-phenylalanine-N-hydroxysuccinimide ester in 200 ml of tetrahydrofuran (THF) was added. The mixture was stirred for 15 hours at room temperature and then solvent was removed under reduced pressure from the reaction mixture. The residue was dissolved in 300 ml of ethyl acetate and the solution was shaken with 100 ml of 0.5 N hydrochloric acid. An organic layer was washed with 100 ml of 5% aqueous solution of sodium bicarbonate and with 100 ml of water, and dried over magnesium sulfate. The drying agent was removed by filtration and thus obtained organic layer was concentrated under reduced pressure to obtain a solid substance. To the residual substance 500 ml of n-hexane were added to produce a gel-like solid substance. The solid substance was obtained by filtration and washed with n-hexane and dried to give tert-butyloxycarbonyl-L-phenylalanyl-L-serine methyl ester. Yield: 36 g (98%), melting point: 90~93 C., specific rotation [alpha]D25 =-0.18 (C=2.75, DMF). Elemental analysis: Calculated for C18 H26 N2 O6 1/4H2 O:C 58.28%, H 7.20%, N 7.55%. Found: C 58.46%, H 7.30%, N 7.43%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetone; acetonitrile; at 20℃; | A solution of the N-hydroxysuccinimide ester of a N-Boc-protected amino acid or a carboxylic acid (48 mmol, 1.2 eq) in acetonitrile or acetone (50 mL) was added slowly to a solution of 3APS, 3-amino-1-propanesulfonic acid, 40 mmol, 1 eq in 2 N NaOH (sodium hydroxide, 23 mL, 1.2 eq). The reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The residual material was stirred with Et2O (diethyl ether, 150 mL) at reflux for 1 h. After the mixture was cooled to room temperature, the solid material was filtered and dried in vacuo, and further purified according to one of the following work-up procedures |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | 317 mg (875 mumol) of 2,5-dioxopyrrolidin-1-yl N-(tert-butoxycarbonyl)-L-phenylalaninate are initially charged together with 13.7 mul of ethyldiisopropylamine in 1 ml of DMF. 50 mg (87 mumol) of the compound of Example 4A dissolved in 5 ml of DMF are added dropwise over a period of 30 min. Stirring at RT for 30 min is followed by concentrating. The residue is eluted by flash chromatography initially with dichloromethane/ethyl acetate eluents in a ratio of 3:1, 2:1 and 1:1. This is followed by elution with pure ethyl acetate and finally with ethanol as eluent. The corresponding fractions which contain still impure target compound are purified and concentrated in vacuo. The residue is then purified once more by preparative HPLC (method 1a). The appropriate fractions are concentrated and dried under high vacuum to obtain 34 mg (50% of theory) of the protected title compound.HPLC (method 2a): Rt=5.34 minLC-MS (method 12): Rt=3.47 min; m/z=782 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 2h; | Example 7: Preparation of Compounds A14, A51, A52(sodium salt), BU, B51(bis(trifluoroacetate) salt) and B52a) Compound A51:Compound A51Step 1: To a mixture of commercial 3-amino-2,2-dimethyl-1-propanol (1.33 g, 13 mmol) in tetrahydrofuran (40 mL) and 1 M aqueous potassium carbonate (10 mL) was added a solution of N-Boc-Phe-O-Succinimide (4.60 g, 13 mmol). The reaction mixture was stirred vigorously at room temperature for 2 h. The two phases were separated and the organic layer was concentrated to afford 3-(N-Boc-L-phenylalaninarnido)-2,2-dimethylpropanol as a white solid ready for use without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; for 15h; | Step 3: To a solution of intermediate from Step 2 (0.90 g, 1.3 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 5 h and concentrated to dryness. Trituration using an ether/hexanes mixture allowed to isolate Compound N18(bis(trifluoroacetate)salt) (0.68, 72% yield) as a white solid. 1H NMR (D2O, 500 MHz) delta in ppm 2.01 (quint, J= 7.0 Hz, 2H), 3.06 & 3.15 (ABX, J= 14.0 & 7.0 Hz, 4H), 3.29-3.42 (m, 4H), 4.07 (t, J= 7.0 Hz, 2H), 7.15-7.30 (m, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of quetiapine free base (0.23 g, 0.6 mmol) in THF (8 mL) was added dropwise LiN(TMS)2 (0.96 mL, 0.96 mmol) and the reaction mixture was stirred for 30 min. at room temperature. A solution of <strong>[3674-06-4]Boc-Phe-OSu</strong> (0.228 g, 0.63 mmol) in THF (4 mL) was added dropwise at room temperature over a period of 5 min. After 2 h, the reaction was quenched with aqueous NH4C1 (50 mL) and stirred for 15 min. The reaction mixture was extracted with EtOAc. The EtOAc layer was washed with aq. NH4CI (2><50 mL), sat. aq. NaHC03 ( 1 chi50 mL) and brine. The organic phase was dried over anhydrous Na2S04 and evaporated to dryness to give Boc-Phe-QTP (0.24 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a stirred solution of NaH (60% in mineral oil, 1.4 mmol, 55 mg) in dry THF (3 mL) was added benzyl malonate (1.05 mmol, 0.27 g) at 0 C and the mixture was stirred 30 min. Then Boc-Xaa-O-Succinimide (0.7 mmol) was added in one portion at 0 C and the mixture was stirred for 2 h at room temperature. Then THF was removed under reduced pressure and replaced with ethyl acetate. The mixture was washed with water (2×30 mL), dried over sodium sulfate and concentrated in vacuo. The product was obtained pure after silica gel chromatography (cyclohexane/ethyl acetate 8:2 as eluant). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In dichloromethane; at 0 - 20℃; for 18h; | A. [(S)-l-(4-Cyano-benzylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester 4-Aminomethylbenzonitrile hydrochloride (1.53g, 9.1mmol) was dissolved in CH2CI2 (100 mL). This solution was cooled to 0 C. (S)-2-tert-Butoxycarbonylamino-3-phenylpropionic acid 2,5- dioxo-pyrrolidin-l-yl ester (3.00g, 8.3mmol) was added followed triethylamine (2.5 lg, 25mmol). After 18 hrs at 0 C to room temperature reaction mixture was diluted with chloroform (100 mL) and washed with NaHC03 ( 1x30 mL), water ( 1x30 mL), brine ( 1x30 mL), dried (Na2S04) and evaporated in vacuo giving a yellow oil. The residue was crystallised from EtO Ac/Pet. Ether (60-80C) to give a white solid identified as [(S)-l-(4-cyano- benzylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (2.71g, 7.1mmol, 86%). [M+H]+ = 380.13 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydrogencarbonate In ethyl acetate for 0.333333h; Milling; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | A reaction mixture of BocPheOSu (163mg, 0.45mmol) in dry THF (2ml) and NEt3 (63muL, 0.45mmol) was stirred for 30min at room temperature under nitrogen atmosphere. A solution of 4-aminoquinoline 5a (100mg, 0.45mmol) and NEt3 (63muL, 0.45mmol) in dry THF (2ml) was then added and the mixture was stirred for 40h at room temperature, under nitrogen atmosphere. The solvent was removed under reduced pressure; water was added and the product was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduce pressure. The residue was purified by flash chromatography on silica gel using as eluent n-hexane/EtOAc (7:3) (180mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 1 mL of radiofluorination reaction mixture was placed into a 10 mL vial and the solvent was evaporated with a flow of argon. 1 mL of CH2Cl2 was then added and evaporated again to dryness. The resulting residue was redissolved in 1 mL of CH2Cl2. The second glass vial (4 mL vial with a screw top) was charged with Sc(OTf)3 (1 eq., 0.04 mmol, 21 mg), DMAP (5 eq., 0.20 mmol, 26 mg) and 0.5 mL of CH2Cl2 and the mixture was stirred 5 min at rt. The solutions from the two vials were combined and the resulting mixture was stirred for additional 2 minutes at room temperature, followed by the addition of Boc-Ala-OSu (5 eq., 0.21 mmol, 60 mg) in one portion, and the mixture was stirred 2 more minutes, providing the diastereomeric material for radio-TLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; | General procedure: A round-bottom flask was charged with amino acid (2.5 mmol), NaHCO3 (5 mmol, or 7.5 mmol in the case of using TFA salt of amino acid) and THF-H2O (1:1,20 mL). A solution of succinimide-activated amino acid (2.75 mmol) in THF (15 mL) was added dropwise to the mixture, and the reaction was stirred at rt for 1-2 days. THF was removed on a rotary evaporator, the reaction mixture was acidified with 0.5 M HCl to pH 2, and the product was extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with water and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the product was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | To a solution of S10 (358 mg, 0.64 mmol) in N,N-dimethylformamide (20 mL) at room temperature was added BOC-Phe-OSu (348 mg, 0.96 mmol) and cesium carbonate (626 mg, 1.92 mmol) and the solution was stirred at room temperature for 12 h. The reaction mixture was filtered and the solids washed with additional N,N-dimethylformamide (10 mL). The filtrate was extracted with ethyl acetate. The organic layers were washed with brine and dried over sodium sulfate. The residue was purified by flash chromatography (1:9 MeOH/CHCl3) to afford compound S11 as a white solid (344 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 20℃; for 16h; | 2?,3?-O-Isopropylidene-5?-O-sulfamoyladenosine S5 (214 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL). After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (72 muL, 0.48 mmol), <strong>[3674-06-4]Boc-Phe-OSu</strong> (175 mg, 0.48 mmol) was added to the reaction mixture. After stirring for at room temperature 16 h, the mixture was concentrated and the residue was taken up in water and extracted with dichloromethane. The organic layers were dried over sodium sulfate, concentrated, and purified by flash chromatography (EtOAc) to afford compound S6 as a white powder (119 mg, 37%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | 41 mg (0.37 mmol) of 2,5-dioxopyrrolidin-1-yl N-(tert-butoxycarbonyl)-L-phenylalaninate were taken up in 10 ml of DMF and admixed with 149 mg (0.41 mmol) of 2-oxa-3-azabicyclo[2.2.2]oct-5-ene (Starting Compound 6) and 72 mul (0.41 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate and extracted by shaking with 5% aqueous citric acid solution and then with 5% aqueous sodium hydrogencarbonate solution. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel with 10:1 toluene/ethanol as the eluent. The corresponding fractions were combined and the solvent was removed under reduced pressure. After the residue had been dried under high vacuum, 69 mg (47% of theory) of the Boc-protected intermediate tert-butyl (2S)-1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-1-oxo-3-phenylpropan-2-yl carbamate were thus obtained as a diastereomer mixture. [2263] LC-MS (Method 1): Rt=1.1 min; MS (ESIpos): m/z=359 (M+H)+. [2264] 64 mg (0.18 mmol) of this intermediate were taken up in 10 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at RT for 30 min. This was followed by concentration under reduced pressure and lyophilization of the remaining residue from water/dioxane. In this way, 66 mg (quant.) of the title compound were obtained as a foam. [2265] HPLC (Method 6): Rt=1.45 min; [2266] LC-MS (Method 3): Rt=1.12 min; MS (ESIpos): m/z=259 (M+H)+ |
47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | [4642] 41 mg (0.37 mmol) of 2,5-dioxopyrrolidin-1-ylN-(tert-butoxycarbonyl)-L-phenylalaninate were taken up in10 ml of DMF and admixed with 149 mg (0.41 mmol) of2-oxa-3-azabicyclo[2.2.2]oct-5-ene (Starting Compound 6)and 72 fll (0.41 mmol) of N,N-diisopropylethylamine. Themixture was stirred at RT for 1 h. The solvent was thenremoved in vacuo, and the residue was taken up in ethylacetate and extracted by shaking with 5% aqueous citric acidsolution and then with 5% aqueous sodium hydrogencarbonatesolution. The organic phase was concentrated, and theresidue was purified by flash chromatography on silica gelwith 10:1 toluene/ethanol as the eluent. The correspondingfractions were combined, and the solvent was removed invacuo. After the residue had been dried under high vacuum,69 mg (47% of theory) of the Boc-protected intermediatetert-butyl-[ (2S)-1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-1-oxo-3-phenylpropan-2-yl]carbamate were thus obtained asa diastereomer mixture.[4643] LC-MS (Method 1): R,=l.l min; MS (ESipos):mz=359 (M+Hr. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | General procedure: Under argon protection, BSA (2.2equiv.) was added to a solution of amino acid (1.1equiv.) in anhydrous dichloromethane. After the mixture was stirred for 1-8h at 23C, a solution of N-Boc protected NHS ester (1equiv.) in dichloromethane was added. The reaction mixture was stirred at 23C under argon until all active ester was consumed as judged by TLC analysis. The reaction mixture was washed with brine, dried over Na2SO4 and concentrated in vacuo to provide a white solid. The isolated product was recrystallized from diethyl ether/n-hexane to yield the targeted dipeptide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.1% | With tetrabutylammonium acetate; In tetrahydrofuran; at 20℃; for 48h;Molecular sieve; | (DMT)-A (26 mg, 45 tmol) was dissolved in 5 mE of tetrahydroffiran (dried with 4 A molecular sieves) in an oven- dried 4-dram reaction vessel. Twenty equivalents of 2a (321 mg, 0.885 mmol) were added to the reaction mixture. TI3AAc (19 mg, 64 jtmol, the reaction catalyst) was added last to the reaction mixture in two separate additions, 6 mg, at the beginning of the reaction, and 1.3mg after the first 24 h of reaction. The reaction stirred under argon overnight at room temperature for 2 days, After evaporation of solvent, the product was purified on silica gel (gradient solvent system; 20-0% petroleum ether in EtOAc, 5% methanol in EtOAc) to give 19.1 mg(52.1%) of a pale-yellow foam after evaporation. ERMS (ESI) calcd mlz for C45H48N609H (MAW 816.9, C45H48N5O9Na (M+Na) 839.3. found 817.4, 839.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; | General procedure: A round-bottom flask was charged with amino acid (2.5 mmol), NaHCO3 (5 mmol, or 7.5 mmol in the case of using TFA salt of amino acid) and THF-H2O (1:1,20 mL). A solution of succinimide-activated amino acid (2.75 mmol) in THF (15 mL) was added dropwise to the mixture, and the reaction was stirred at rt for 1-2 days. THF was removed on a rotary evaporator, the reaction mixture was acidified with 0.5 M HCl to pH 2, and the product was extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with water and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the product was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; dmap; In tetrahydrofuran; at 80℃; for 24h;Inert atmosphere; | Preparation of (S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoic acid (S)-Lactic acid (597 mg, 6.62 mmol), (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (2.00 g, 5.52 mmol), 4-(dimethylamino)pyridine (67 mg, 0.552 mmol), pyridine (437 mg, 5.52 mmol), and tetrahydrofuran (35 mL) were combined and heated at 80 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=3 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoic acid (2.02 g, quantitative) as a colorless semi-solid: 1H NMR (300 MHz, CDCl3) delta 7.34-7.18 (m, 5H), 5.24-5.19 (m, 1H), 4.90 (m, 1H), 4.61 (m, 1H), 3.25 (dd, J=14.1, 8.7 Hz, 1H), 3.07 (m, 1H), 1.55 (d, J=8.7 Hz, 3H), 1.39 (s, 9H), CO2H proton not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.25h;Inert atmosphere; | Preparation of (S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl 2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate A solution of (S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl 2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (134 mg, 0.195 mmol) and (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (109 mg, 0.301 mmol) in methylene chloride (3 mL) was treated with N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) and stirred under a nitrogen atmosphere for 15 min. After this time, the reaction mixture was diluted with methylene chloride (15 mL) and washed with saturated aqueous ammonium chloride (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl 2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate (156 mg, quantitative) as a colorless semi-solid: ESI MS m/z 706 [C38H47N3O10+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere; | A solution of (S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl 2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (121 mg, 0.233 mmol) in tetrahydrofuran (6 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (98 mg, 0.28 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) at 0 C. and stirred under a nitrogen atmosphere for 1 h. After this time, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (40 g silica gel column, 0-20% methanol/methylene chloride) to provide (S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl 2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate (45 mg, 28%) as a white solid: ESI MS m/z 692 [C37H45N3O10+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydrogencarbonate; In ethyl acetate; for 1h;Milling; | Boc-L-phenylalanine N-hydroxysuccinimide ester (140 mg, 0.38 mmol), L-prolinemethyl ester hydrochloride 2 (63 mg, 0.38 mmol, 1.0 equiv), NaHCO3 (48 mg, 0.57 mmol, 1.5eq) and EtOAc (270 L, = 1.07 L.mg-1) as liquid assistant were introduced in a 10 mL stainless steel grinding jar with one stainless steel ball (10 mm diameter). The jar was closed and submitted to vibration milling for 1 h at 30 Hz. The residue was then dissolved in EtOAc andwater, the layers were separated and the aqueous phase was extracted once with EtOAc.The combined organic phases were washed twice with 1 N aqueous NaOH solution, twice with 1 N aqueous HCl solution and once with brine. After drying over MgSO4, filtration and evaporation under vacuum, the dipeptide Boc-Phe-Pro-OMe 4 (118 mg, 0.31 mmol, 82%) was obtained as a colorless wax. Analytical data were in agreement with those reported inthe literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: The general scheme for the synthesis of AA-CAMderivatives is shown in Fig. S1 and the details ofchemical synthesis are provided in the SupplementaryMethods section. CAM [(1R,2R)-2-amino-1-(4--nitrophenyl)propane-1,3-diol)] was prepared asdescribed previously [23]. Amino acids with protectedalpha- and side-chain amino groups wereactivated by reaction with N-hydroxysuccinimide inthe presence of N,N?-dicyclohexylcarbodiimide at0 C. The resulting succinimide-reactive esters wereused for the acylation of CAM in the presence ofdiisopropylethylamine as a base at room temperature.Subsequent deprotection was achieved bytreatment of the obtained amino-acid CAM derivativeswith trifluoroacetic acid and appropriate scavengers.Synthesized AA-CAM derivatives were purifiedby columnchromatography on silica gel using suitablesystems of solvents. For generating N-acetylatedvariants of AA-CAM, additional acetylation wasperformed by reacting the unprotected AA-CAMderivatives with the N-acetylsuccinimide. Purity andchemical structures of obtained compounds wereconfirmed by HPLC, LC-MS, and NMR spectroscopy(see Supplementary Methods). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In this example, dopamine by adding dopamine · HCl (19 g) to acetone (200 mL). HCl solution was prepared. Water (200 mL) and sodium hydrogencarbonate (R0090, 50 g) were added to the dopamine · HCl solution to obtain a first mixture. Next, boc-phenylalanine N-hydroxysuccinimide ester (<strong>[3674-06-4]Boc-Phe-OSu</strong>, 36 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a third solution. Sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined, first pyridine (R 0081, 30 mL), then benzoyl chloride (R 0 488, 30 g) was added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 hours and then poured into water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL) 100 mL), and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered off and washed with ethyl acetate to give a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution and then HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain 4- (2- (2-amino-3-phenylpropanamido) ethyl) -1,2-phenylenedibenzoate hydrochloride. | ||
In this example, dopamine.HCl (19 g) was added to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine / HCl solution to obtain a first mixture. Then boc-phenylalanine N-hydroxysuccinimide ester (<strong>[3674-06-4]Boc-Phe-OSu</strong>, 36 g) was added to the first mixture to give a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. Then sodium sulfate was filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to give a fifth mixture. The fifth mixture was stirred at RT for 2 h then water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x. Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2-amino-3-phenylpropanamide) ethyl) -1,2-phenylenedibenzoate hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 1.5 g (6.9 mmol) of 12-aminododecanoic acid and 1.5 g (6.9 mmol) of N-(tert-butoxycarbonyl)-L-phenylalanine succinimidyl (hereinafter referred to as "<strong>[3674-06-4]Boc-Phe-OSu</strong>") were dissolved in a mixed solution of 150 mL of methanol and 50 mL of THF, 2.5 g (6.9 mmol), or N-(benzyloxycarbonyl)-L-phenylalanine succinimidyl (hereinafter referred to as "Z-Phe-OSu ")2.7 g (6.9 mmol) was stirred for several hours. After distilling off the solvent, the citric acid aqueous solution and the remaining solids with water were successively washed and filtered and vacuum-dried.0.7 g (6.9 mmol) of triethylamine and the condensation agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter referred to as "DMT-MM" The resulting solid and 1.4 g (6.9 mmol) of HCl · H2N - Gly Gly - COOEt were stirred overnight in the presence of 1.9 g (6.9 mmol) methanol. After distilling off the solvent, the citric acid aqueous solution, the sodium hydrogen carbonate aqueous solution, and the solid remaining with water were successively washed and filtered and dried under vacuum to obtain a product.From 1 H-NMR, it was confirmed that this product was the desired product 1-Phe-X (3.6 g (5.9 mmol), yield 86%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 1h; | To a solution of compound 12A (70 mg, 143.02 umol, TFA) and (2,5- dioxopyrroiidin- 1 -yi) (2,5)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate (104 mg, 286.04 urnol) in DMT (3 mL) was added DIEA (715.10 nmol, 0.12 mL), the mixture was stirred at 15 C for Ih. The reaction mixture was diluted with water (30 mL), extracted with EA (10 mL x 3), the organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to give a residue. The residue was purified by preparatory- TLC (DCM: MeOH = 10: 1). Compound 14 (15 mg, yield: 15.5%) as white solid was obtained. lH NMR (400MHz, DMSO- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; | 5 (N2-((tert-butoxycarbonyl)-l-phenylalanyl)-Nw-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-d-arginine). Compound 3 (0.93 g,2.57 mmol, 1.1 eq) was added to a solution ofd-Arg(Pbf)-OH (4) (1.00 g, 2.34 mmol, 1.0 eq)and triethylamine (1.30 mL, 9.37 mmol, 4.0 eq)in DMF (50 mL). The reaction was stirred at room temperature for 24 h. The solvent was removed underreduced pressure and the crude product was purifiedby column chromatography using a gradient ofEtOH/NH4OH/DCM/Pet. Et. from13.7:1.7:71.9:12.7to 23.5:4.7:62.5:9.4 as eluents. Yield 75%. 1H NMR(400 MHz, Methanol-d4) δ 7.22 (d, J = 6.1 Hz, 5H),7.19-7.11 (m, 1H), 4.29 (d, J = 6.1 Hz, 1H), 4.23 (s,1H), 3.11 (dd, J = 13.7, 5.5 Hz, 3H), 2.99 (s, 2H), 2.82(dd, J = 13.7, 8.8 Hz, 1H), 2.58 (s, 3H), 2.52 (s, 3H),2.08 (s, 3H), 1.75 (s, 1H), 1.56 (dt, J = 13.7, 7.5 Hz,1H), 1.45-1.29 (m, 15H). 13C NMR (101 MHz,Methanol-d4) δ 173.63, 159.84, 157.52, 139.40,138.65, 134.39, 133.49, 130.45, 130.35, 129.47,129.26, 127.72, 127.52, 126.02, 118.44, 87.64, 80.70,57.77, 54.45, 43.97, 39.39, 30.56, 28.74, 28.70,28.66, 26.44, 19.65, 18.43, 12.56. HRMS Calculated[M + H]: 674.3218; Found [M + H]; 674.3208. |
75% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; | 5 (N2-((tert-butoxycarbonyl)-l-phenylalanyl)-Nw-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-d-arginine). Compound 3 (0.93 g,2.57 mmol, 1.1 eq) was added to a solution ofd-Arg(Pbf)-OH (4) (1.00 g, 2.34 mmol, 1.0 eq)and triethylamine (1.30 mL, 9.37 mmol, 4.0 eq)in DMF (50 mL). The reaction was stirred at room temperature for 24 h. The solvent was removed underreduced pressure and the crude product was purifiedby column chromatography using a gradient ofEtOH/NH4OH/DCM/Pet. Et. from13.7:1.7:71.9:12.7to 23.5:4.7:62.5:9.4 as eluents. Yield 75%. 1H NMR(400 MHz, Methanol-d4) δ 7.22 (d, J = 6.1 Hz, 5H),7.19-7.11 (m, 1H), 4.29 (d, J = 6.1 Hz, 1H), 4.23 (s,1H), 3.11 (dd, J = 13.7, 5.5 Hz, 3H), 2.99 (s, 2H), 2.82(dd, J = 13.7, 8.8 Hz, 1H), 2.58 (s, 3H), 2.52 (s, 3H),2.08 (s, 3H), 1.75 (s, 1H), 1.56 (dt, J = 13.7, 7.5 Hz,1H), 1.45-1.29 (m, 15H). 13C NMR (101 MHz,Methanol-d4) δ 173.63, 159.84, 157.52, 139.40,138.65, 134.39, 133.49, 130.45, 130.35, 129.47,129.26, 127.72, 127.52, 126.02, 118.44, 87.64, 80.70,57.77, 54.45, 43.97, 39.39, 30.56, 28.74, 28.70,28.66, 26.44, 19.65, 18.43, 12.56. HRMS Calculated[M + H]: 674.3218; Found [M + H]; 674.3208. |
Tags: 3674-06-4 synthesis path| 3674-06-4 SDS| 3674-06-4 COA| 3674-06-4 purity| 3674-06-4 application| 3674-06-4 NMR| 3674-06-4 COA| 3674-06-4 structure
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P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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